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Abstract

The FIELD study randomised 9795 patients with DM to fenofibrate or placebo. Fenofibrate was associated with an 11% relative risk reduction (RRR) in total CVD events (hazard ratio [HR] 0.89, 95% CI 0.80 – 0.99; p=0.035) and a nonsignificant 11% reduction in the primary outcome, coronary events (coronary heart disease death or nonfatal myocardial infarction (MI)), (HR 0.89, 0.75–1.05; p=0.16), Lancet 2005; 366 ;1849–61. However a greater uptake of other drugs, especially statins, among patients assigned placebo meant intention-to-treat effects of fenofibrate were attentuated. For patients who took other drugs, we assumed future CVD events were reduced by 25% by statins (based on randomised trial evidence), by 20% for a first other major CVD drug (antihypertensives, antiplatelets) and by 15% for additional CVD drugs. Fenofibrate effects were adjusted for uptake of other drugs by applying these estimates to each patient for the period from drug commencement. Fenofibrate effects were then also adjusted for those discontinuing fenofibrate (adjusted for drop-out: Stat Med 1988; 7 :1179). Among 4895 assigned fenofibrate average non-usage of the study drug over the 5 year trial period was 11%, while statin use was 8%. Among 4900 assigned placebo, statin use was 16%. There was a slightly greater use of other CVD drugs in the placebo group (1 to 3% extra). After adjustment for these additional therapies, statistical evidence of treatment benefit was stronger and the effect of fenofibrate on coronary and total CVD events was greater (table⇓). Further, the excess of CVD deaths associated with fenofibrate was reduced and remains consistent with a chance imbalance. Effects of fenofibrate on CVD events were underestimated in the original analysis. Adjusted results suggest a plausible 15% reduction of CVD events with fenofibrate. The methods used preserve comparisons between the randomised groups and are applicable to other long-term trials.